Abstract Although still controversial, there is growing evidence that electronic cigarettes (e-cigs) can help smokers reduce the number of cigarettes they smoke per day or quit completely. Regular e-cig users report that the variety of flavors, like fruit and dessert flavors, help to curb cigarette cravings and maintain abstinence. Along with the potential for flavors to help smokers switch to e-cigs, appealing flavors have also been identified as a primary contributor to the initiation of e-cig use among youth. The FDA is calling for more information on how flavors affect the addictive potential of e-cigs to determine if flavor is a necessary feature for satisfying adult smokers. However, there remains a critical need for new, innovative methods of measuring the addictive potential of tobacco products. Compulsive drug-seeking behavior is known to be driven by neuroadaptations in the brain that can serve as early markers of addiction development. A neurobehavioral process that occurs across substances of abuse is the development of conditioned reactivity to drug cues. Drug cues alone can elicit craving, drug- seeking behavior, and relapse. Cue-reactivity is mediated by neuroadaptations in mesocorticolimbic circuitry that occur when environmental and sensory stimuli become associated with the dopaminergic effects of the drug. Using functional magnetic resonance imaging (fMRI), our group was the first to show evidence of neural reactivity to visual e-cig images among regular e-cig users. Given that food-related flavors independently elicit reactivity throughout reward and learning brain circuitry that drives conditioning, fruit and dessert e-cig flavors have the potential to significantly enhance e-cig cue conditioning. The current study aims to establish proof-of-concept that neural cue-reactivity can serve as an early, objective marker of the addictive potential of e-cigs. Further, this proposal will examine the effect of flavor and nicotine concentration on the addictive potential of e-cigs to aid research informing FDA regulations on e-cig flavors and smoking cessation treatment. E-cig nave smokers (n=56) will be randomized to exclusively use an e-cig with tobacco or apple cinnamon flavored e-liquid containing 15 or 0 mg/ml of nicotine for four weeks. We will use state-of-the-art olfactory fMRI equipment at the Penn State Center for Nuclear Magnetic Resonance Research to examine changes in neural cue-reactivity before and after the 4-week conditioning phase. The central hypothesis underlying this award is that flavor type and nicotine level can alter the addictive potential of e-cigs by enhancing or diminishing conditioned reactivity to e-cig cues. The principal investigator is an early career researcher supported by a NIDA K23 career development award to obtain training in new neuroimaging modalities for tobacco research. The data collected will inform larger trials investigating the role of flavor characteristics in altering the abuse liability of e-cigs and assisting smokers? use of e-cigs as a harm reduction or cessation aid.